On June 5, 2017 AVEO Oncology (NASDAQ: AVEO) and Biodesix, Inc., co-development partners, reported the presentation of results from two investigator-sponsored Phase 1 studies of ficlatuzumab at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago, Illinois (Press release, AVEO, JUN 5, 2017, View Source [SID1234519391]). The first is a study of ficlatuzumab in combination with the EGFR inhibitor cetuximab in patients with cetuximab-resistant, metastatic head and neck squamous cell carcinoma (HNSCC), and the second is a study of ficlatuzumab in combination with high-dose cytarabine in patients with high risk relapsed or refractory acute myeloid leukemia (AML). Ficlatuzumab is a humanized IgG1 antibody that binds to the HGF ligand with high affinity and specificity to inhibit the biological activities of the HGF/c-Met pathway.

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"HGF is an important pathway for resistance and proliferation in a number of cancer models, serving as a means to overcome EGFR inhibition in HNSCC, and as an adverse prognostic factor in AML," said Michael Needle, chief medical officer of AVEO. "In a Phase 1 study in patients with cetuximab-resistant recurrent/metastatic HNSCC, the addition of ficlatuzumab to the EGFR-targeted antibody cetuximab resulted in a disease control rate of 67%, and prolonged progression free and overall survival compared to historical controls, in addition to being well tolerated. With continued, strong investigator support, we look forward to the expected initiation, in the second half of 2017, of a randomized, Phase 2, multicenter, investigator-initiated trial to confirm these findings. We also look forward to the completion of the ongoing investigator-sponsored study in AML, which has demonstrated early signs of tolerability and activity, including a 50% complete response rate in the relapsed/refractory setting."

"Median PFS for cetuximab monotherapy in the naïve setting is only two months, as with the median PFS for nivolumab or single-agent chemotherapy in the platinum-refractory setting, suggesting an urgent need for new therapies," said Julie E. Bauman, MD, MPH, Professor of Medicine, Chief, Division of Hematology/Oncology, Associate Director of Translational Research, University of Arizona Cancer Center. "Although a small cohort, the fact that we observed significant responses and PFS of 6 months in a refractory population in this study suggests important biologic activity."

AVEO also announced that a Trials in Progress presentation highlighting the ongoing Phase 3, randomized, controlled, multi-center, open-label TIVO-3 study comparing tivozanib, the Company’s potent, selective, long half-life inhibitor of all three vascular endothelial growth factor (VEGF) receptors, to sorafenib in subjects with refractory advanced renal cell carcinoma.

The posters are available at www.aveooncology.com. Details of the posters are below:

Phase I study of the anti-HGF mononclonal antibody (mAb), ficlatuzumab, and cetuximab in cetuximab-resistant, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)

Presenter: Julie E. Bauman, MD, MPH, Chief, Division of Hematology and Oncology, Associate Director, Translational Research, University of Arizona Cancer Center
Abstract Number: 6038
Session: Head and Neck Cancer
Date and Time: Monday, June 5, 2017, 1:15-4:45 PM CT

In this phase I study, 12 patients with R/M HNSCC who had disease recurrence within 6 months of cetuximab radiation or progression within 6 months of cetuximab treatment in the recurrent metastatic setting were treated with a ficlatuzumab/cetuximab combination. The primary objective was to establish the recommended Phase 2 dose (RP2D) for ficlatuzumab, with the secondary objectives being to evaluate preliminary clinical efficacy of RP2D and to evaluate the relationship between preliminary efficacy and 1) baseline tumor p-Met expression and 2) serum Veristrat.

Cetuximab was administered every 2 weeks at 500 mg/m2, and ficlatuzumab dose tiers were 10 mg/kg (tier 1) or 20 mg/kg IV every 2 weeks (tier 2), with inter-patient escalation or de-escalation based on cumulative dose-limiting toxicities (DLT). RP2D was set at tier 2 if no DLTs were observed after 8 enrolled patients, with expansion continuing to 12 patients. Three patients were treated at dose tier 1 and 9 at dose tier 2. The RP2D is ficlatuzumab 20 mg/kg and cetuximab 500 mg/m2 every 2 weeks. The overall response rate was 17% (1 PR at tier 1; 1 at tier 2) and 50% of patients had stable disease, for a disease control rate of 67%. Median PFS and OS at RP2D were 6.0 mos (90% CI=2 mos-NR) and 8.2 mos (90% CI=2.7 mos-NR).

CyFi: A phase I study exploring the role of cMET pathway inhibition with ficlatuzumab (Fi) combined with high-dose cytarabine (Cy) in patients with high risk relapsed or refractory acute myeloid leukemia (AML)

Presenter: Charalambos (Babid) Andreadis, MD, Hematologic Malignancies and Blood and Marrow Transplantation Program, University of California, San Francisco
Abstract Number: 7040
Session: Hematologic Malignancies – Leukemia, Myelodyplastic Syndromes, and Allotransplant
Date and Time: Monday, June 5, 2017, 8:00-11:30 AM CT

In this ongoing study, the safety and tolerability of ficlatuzumab in combination with cytarabine was assessed in 9 patients with high risk relapsed or refractory acute myeloid leukemia. Ficlatuzumab was given in escalated dosing of 10, 15, or 20 mg/kg for 4 doses every 2 weeks, starting on day 0, and cytarabine was given at a fixed dose of 2g/m2 on days 2-7, using a 3×3 design. Dose-limiting toxicity (DLT) was defined based on toxicities attributable to the combination and unexpected with AML or high-dose cytarabine. Peripheral blood mononuclear cells and serum were collected at defined time points to assess HGF levels and activation of the c-Met pathway. The results showed no DLTs, and the combination has proven well tolerated. The most frequent grade 3-4 adverse events were febrile neutropenia (56%), ventricular tachycardia (22%), respiratory distress (11%), electrolyte disturbance (11%). There was 1 death from sepsis and multi-organ failure on day 23, during count recovery. Of the 8 evaluable patients, 4 achieved a CR (50%), all in the 2nd dose cohort. All patients had detectable circulating HGF levels at baseline and levels increased following exposure to Fi by an average of 193% (p value). Baseline levels or change from baseline were not associated with response.

Title: Tivo-3: A phase 3, randomized, controlled, multi-center, open-label study to compare tivozanib hydrochloride to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC)
Presenter: Brian I. Rini, MD, FACP, Professor of Medicine, Lerner College of Medicine, Leader, GU Program, Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute
Abstract Number: TPS4600
Session: Genitourinary (Non-prostate) Cancer
Date and Time: Sunday, June 4, 2017, 8:00-11:30 AM CT

About Ficlatuzumab

Ficlatuzumab (formerly known as AV-299) is a potent hepatocyte growth factor (HGF) inhibitory antibody that binds to the HGF ligand with high affinity and specificity to inhibit HGF/c-Met biological activities. AVEO and Biodesix, Inc. currently divide all worldwide development costs for ficlatuzumab and are seeking a commercialization partner. Ficlatuzumab is currently being evaluated in investigator-sponsored trials in squamous cell carcinoma of the head and neck (HNSCC) and acute myeloid leukemia (AML).

About Tivozanib

Tivozanib is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers

On June 5, 2017 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported an oral presentation on updated data from its NY-ESO study in synovial sarcoma, as well as four trials in progress posters (Press release, Adaptimmune, JUN 5, 2017, View Source [SID1234519390]). The data were presented at the 2017 ASCO (Free ASCO Whitepaper) annual meeting in Chicago, Illinois.

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The Company will host a live teleconference and webcast slide presentation on June 6th from 8:00–9:00 AM EDT (1:00–2:00 PM BST) to discuss the updated synovial sarcoma clinical data. Call in details and the webcast link are provided below.

"We have seen responses across all of our ongoing cohorts in our NY-ESO study in synovial sarcoma, including in patients who express lower levels of NY‑ESO, and in those receiving conditioning with modified doses of fludarabine / cyclophosphamide," said Rafael Amado, Adaptimmune’s Chief Medical Officer. "A lower response rate was observed in the absence of fludarabine conditioning and that cohort is now closed. For patients from Cohort 1, an updated survival analysis shows a promising median predicted overall survival of 120 weeks or approximately 28 months. The data continue to suggest that NY-ESO is well-tolerated. We have seen no events of seizure, cerebral edema, or encephalopathy; most events of cytokine release syndrome are grades 1-2 and all resolved with supportive care."

He continued: "We are in a period of significant operational momentum with ongoing trials in our three wholly-owned assets, MAGE‑A4, MAGE-A10 and AFP, as well as additional studies through our collaboration with GSK with NY-ESO in myxoid / round cell liposarcoma, ovarian, and non-small cell lung cancer – study designs and screening progress for some of these trials were also presented at ASCO (Free ASCO Whitepaper)."

Data Update from the Ongoing NY-ESO Synovial Sarcoma Study
During an oral presentation on June 5th entitled, "Open label, non-randomized, multi-cohort pilot study of genetically engineered NY-ESO-1 specific NY-ESO-1c259t in HLA-A2+ patients with synovial sarcoma (NCT01343043)," Dr. Sandra P. D’Angelo of the Memorial Sloan Kettering Cancer Center presented an update on all cohorts from Adaptimmune’s ongoing study.

NY-ESO continues to be generally well-tolerated and initial anti-tumor activity has been observed in all ongoing cohorts including low expressors of NY‑ESO (Cohort 2)
Of the twelve patients treated in Cohort 1 (non-modified fludarabine / cyclophosphamide ["Flu/Cy"] lymphodepletion regimen), five remain alive with a median predicted overall survival of 120 weeks (~28 months) (data cutoff March 30, 2017)
Confirmed responses have been observed in all cohorts as follows:
— Cohort 1 (High Flu/Cy, High NY-ESO): 6/12 (50%) patients with a median progression free survival (PFS) of 15 weeks (range:8, 38); 6/10 (60%) response rate in patients who received a target dose of at least one billion cells
— Cohort 2 (High Flu/Cy, Low NY-ESO): 2/5 (40%); ongoing
— Cohort 3: (High cyclophosphamide, no fludarabine, High NY-ESO): 1/5 (20%); cohort closed
— Cohort 4 (Modified Flu/Cy, High NY-ESO): 3/6 (50%); (ongoing)
Peak and long-term expansion of NY-ESO SPEAR T-cells appears to correlate with clinical efficacy
Fludarabine appears to be an important component of the lymphodepletion regimen
All reported events of cytokine release syndrome resolved with supportive care, and the majority of events were Grade 1 or 2
There were no reported events of seizure, cerebral edema, or encephalopathy
Overview of Study Designs from the Trials in Progress Posters
The four trials in progress posters summarized the study designs for Adaptimmune’s ongoing NY‑ESO trials in myxoid/round cell liposarcoma (MRCLS), ovarian cancer, and non-small cell lung cancer (NSCLC); the Company’s ongoing MAGE-A10 trial in NSCLC, and its MAGE-A10 triple tumor study in patients with head and neck, melanoma, or urothelial "bladder" tumors.

NY-ESO in MRCLS (NCT02992743):
— Open-label, non-randomized pilot study evaluating the safety, tolerability, and antitumor activity of NY-ESO SPEAR T-cells in patients with MRCLS
— Initially, 10 subjects are planned to be enrolled, with potential to enroll an additional 5 subjects. Subjects who do not receive the minimum cell dose or who do not receive the T‑cell infusion may be replaced.
— Subjects must be: ≥ 18 yrs old; HLA-A*02:01, *02:05, or *02:06 positive; have advanced (metastatic or inoperable) MRCLS expressing NY-ESO-1 at 2+/3+ intensity in ≥30% of tumor cells by IHC; measurable disease; prior systemic anthracycline therapy; have ECOG status 0 or 1; and adequate organ function.
— Lymphodepletion regimen: fludarabine (30mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days; same as Cohort 4 in Synovial Sarcoma study
— Target dose of 1 – 8 × 109 transduced SPEAR T-cells
— Efficacy assessed by overall response rate, time to response, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months until confirmation of disease progression
— This study is open and actively enrolling; as of May 18, 2017, 3 subjects have been enrolled

NY-ESO in Ovarian Cancer (NCT01567891):
— Single-arm, open-label clinical trial evaluating the safety, tolerability, and antitumor activity of NY-ESO SPEAR T-cells in patients with ovarian cancer
— Subjects must be ≥ 18 years old; HLA-A*02:01, *02:05, or *02:06 positive; have recurrent epithelial ovarian, primary peritoneal or fallopian tube carcinoma with refractory or platinum-resistant disease expressing NY-ESO-1 at ≥1+ intensity in ≥10% of tumor cells by IHC; have measurable disease; have ECOG status 0 or 1; and have adequate organ function.
— The study evaluates two lymphodepleting regimens: cyclophosphamide alone (enrollment completed; n=7) and cyclophosphamide plus fludarabine (up to 10 subjects to be treated)
— The first 6 subjects were lymphodepleted prior to T-cell infusion with various regimens of cyclophosphamide alone. None of these subjects achieved a response per RECIST v1.1 (ASCO 2016).
— The lymphodepletion regimen has been amended to include both fludarabine and cyclophosphamide (fludarabine [30mg/m2/day] and cyclophosphamide [600 mg/m2/day] for 3 days; same as Cohort 4 in Synovial Sarcoma study)
— Target dose of 1 – 6 × 109 transduced SPEAR T-cells
— Efficacy assessed by response rate, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months until confirmation of disease progression
— Enrollment is ongoing
NY-ESO (NCT02588612) and MAGE-A10 (NCT02592577) in NSCLC:
— Open-label studies of NY-ESO or MAGE A-10 SPEAR T-cells in patients with NSCLC
— Subjects are screened under a separate protocol (Screening Protocol: NCT02636855) to identify those who have the relevant HLA-A*02 alleles and NY-ESO-1 or MAGE-A10 tumor expression.
— Subjects must have Stage IIIb or IV NSCLC, have failed at least one platinum-containing regimen (may have received CPIs), have measurable disease, ECOG 0-1, adequate organ function, and be without brain metastases, history of severe autoimmune disease or current uncontrolled illness
— The NY-ESO trial is a 10 subject study with a target dose of 1-6 x 109 transduced cells
— The MAGE-A10 trial is a first-in-human study utilizing a modified 3+3 design in up to 28 patients with escalating doses of 0.1, 1.0 and 1-6 x 109 transduced T-cells to evaluate safety, including dose limiting toxicities (DLTs). The DLT observation period will be during the first 30 days following SPEAR T-cell infusion for each patient in all groups.
— For the NY-ESO study, the lymphodepletion regimen is: fludarabine (30mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days; same as Cohort 4 in Synovial Sarcoma study
— For the MAGE-A10 study, the lymphodepletion regimen for the first group is cyclophosphamide alone : cyclophosphamide (1800 mg/m2/day) for 2 days; subsequent groups will receive fludarabine (30mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days; same as Cohort 4 in Synovial Sarcoma study
— For both studies, efficacy assessed by response rate, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months (for 2 years) and then every 6 months until confirmation of disease progression
— These studies are currently active and enrolling; as of May 18, 2017, 3 subjects have been enrolled in the NY-ESO-1 study and 2 subjects have been enrolled in the MAGE-A10 study

MAGE-A10 Triple Tumor (NCT02989064):
— Open-label first-in-human study utilizing a modified 3+3 design in up to 10 patients receiving the target dose with escalating doses of 0.1, 1.0 and 1-6 x 109 transduced T-cells to evaluate safety, including DLTs. The DLT observation period will be during the first 30 days following SPEAR T-cell infusion for each patient in all groups.
— Subjects are screened under a separate protocol (Screening Protocol: NCT02636855).
— Subjects must be HLA*02:01 and/or *02:06 positive and have inoperable or metastatic (advanced) urothelial "bladder" cancer, melanoma, or squamous cell head and neck tumors with MAGE-A10 expression at ≥1+ intensity in ≥10% of tumor cells by IHC; and, have received standard of care therapies and have progressive disease.
— Lymphodepletion regimen: fludarabine (30mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days; same as Cohort 4 in Synovial Sarcoma study
— Efficacy assessed by overall response rate, best overall response, time to response, duration of response, duration of stable disease, progression-free survival, and overall survival at weeks 6, 12, 18, and 24 weeks, and then every 3 months until confirmation of disease progression
— This study is currently active and enrolling; as of May 18, 2017, 4 subjects have been enrolled

On June 5, 2017 Kite Pharma, Inc., (Nasdaq:KITE), a leading cell therapy company, reported that 73 percent of patients achieved complete remission, including those with incomplete or partial recovery of bone marrow, in an updated analysis of the Phase 1 ZUMA-3 trial of KTE-C19 in adults with high burden relapsed/refractory acute lymphoblastic leukemia (r/r ALL) (Press release, Kite Pharma, JUN 5, 2017, View Source [SID1234519386]). All responders tested negative for minimal residual disease (MRD). The data were presented today in a poster session at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL and follow previously reported results from the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2016.

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In the Phase 1 trial, 11 patients were treated with KTE-C19 at two target dose levels (2.0×106/kg and 1.0×106/kg). No dose-limiting toxicities (DLT) occurred in the trial. Both doses were tolerable and responses were achieved at each level. Ongoing complete remissions have been observed at 2.0+ to 7.4+ months.

"The majority of adult patients diagnosed with ALL will experience disease relapse and subsequently face a poor prognosis," said David Chang M.D., Ph.D., Executive Vice President, Research and Development, and Chief Medical Officer of Kite. "We are encouraged by the results from the ZUMA-3 trial to date in this extremely difficult-to-treat patient population. Before launching a pivotal Phase 2 study, we plan to optimize the cell dose of this potentially life-saving therapy for patients with significant unmet need."

Three of 11 (27 percent) patients had grade 3 or higher cytokine release syndrome (CRS) and six of 11 (55 percent) had grade 3 or higher neurologic events. These adverse events were generally reversible. As previously reported at ASH (Free ASH Whitepaper) 2016, one patient experienced fatal CRS. In order to further improve the safety profile of KTE-C19, ZUMA-3 is also evaluating additional patients who will receive tocilizumab within 36 hours post-KTE-C19 infusion, and a lower dose of 0.5×106 CAR T cells/kg.

KTE-C19 was successfully manufactured in this multi-center trial for all patients in six days across a range of absolute lymphocyte and blast counts in a centralized and streamlined process. Responses were observed across a wide range of CD4:CD8 ratios and T-cell phenotypes.

Kite plans to initiate Phase 2 of the ZUMA-3 trial in 2017.

Poster Presentation Details

Updated results from ZUMA-3: A phase 1/2 study of KTE-C19 chimeric antigen receptor (CAR) T cell therapy in adults with high-burden relapsed/refractory acute lymphoblastic leukemia (R/R ALL)

Abstract #3024
Session: Poster Session: Developmental Therapeutics – Immunotherapy
Poster Board #119
Session Time/Location: Monday, June 5, 2017: 8:00-11:30 AM CDT, Hall A
Presenter: Bijal D. Shah, M.D., Moffitt Cancer Center, Tampa, FL
About axicabtagene ciloleucel/KTE-C19

Kite’s lead product candidate, axicabtagene ciloleucel, also known as KTE-C19, is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. Axicabtagene ciloleucel has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

On June 5, 2017 Incyte Corporation (Nasdaq:INCY) and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that updated data from the ongoing Phase 1/2 ECHO-202 trial evaluating epacadostat, Incyte’s selective IDO1 enzyme inhibitor, in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, will be highlighted in multiple presentations at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Incyte, JUN 5, 2017, View Source [SID1234519385]). Updated efficacy data at ASCO (Free ASCO Whitepaper) are from multiple tumor cohorts – metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN), advanced urothelial bladder cancer (UC) and advanced renal cell carcinoma (RCC) – as well as a pooled safety analysis (Phase 2) of the total study population (across all tumor cohorts). Data will be highlighted in two oral presentations (SCCHN and UC) and two poster discussions (RCC and pooled safety).

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"We are pleased to report additional data from multiple tumor-specific cohorts of our Phase 1/2 ECHO-202 trial, which continue to provide encouraging efficacy and safety data for this investigational treatment combination," said Steven Stein, M.D., Chief Medical Officer, Incyte. "These and other data presented here in Chicago underscore the potential of this novel investigational immunotherapy combination in multiple advanced cancers, supporting the advancement of our clinical development program for epacadostat and KEYTRUDA into multiple Phase 3 clinical trials."
Efficacy Data from ECHO-202 (Abstract #6010, #4503, #4515)
Results of these tumor cohorts (as of February 27, 2017) include:

SCCHN
(Abstract #6010)
UC
(Abstract #4503)
RCC
(Abstract #4515)
Total Subgroup
N (%)
Prior Lines of Treatment
N (%)
Total Subgroup
N (%)
Prior Lines of Treatment
N (%)
Total Subgroup
N (%)
Prior Lines of Treatment
N (%)
Total 1-2
>3
Total 0-1 ≥2 Total 0-1 ≥2
ORR 13/38
(34)

3 CR
10 PR
12/31
(39)

3 CR
9 PR
1/7
(14)

1 PR 14/40
(35)

3 CR
11 PR 12/32
(38)

3 CR
9 PR
2/8
(25)

2 PR 10/30
(33)

1 CR
9 PR 9/19
(47)

1 CR
8 PR 1/11
(9)

1 PR
DCR
23/38
(61)
20/31
(65)
3/7
(43)
21/40
(53)
19/32
(59)
2/8
(25)
15/30
(50)
11/19
(58)
4/11
(36)
DoR 10/13 responses ongoing
Median range: 18.4+ (7.1 to 90.3+) weeks
10/14 responses ongoing
Median range: 30.6+ (9.7 to 93.1+) weeks
7/10 responses ongoing
Median range: 26.8+ (18.1+ to 53.1) weeks

Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), Complete Response (CR), Partial Response (PR)
Safety Data from ECHO-202 (Abstract #3012)
In addition to the efficacy data above, an updated pooled analysis evaluated 294 patients with advanced cancers in the ECHO-202 Phase 2 safety population. Treatment-related adverse events (TRAEs) occurred in 67 percent (n=197/294) of patients. The most common TRAEs included fatigue (29%), rash (17%), nausea (11%) and pruritus (10%). Grade ≥3 TRAEs occurred in 18 percent (n=52/294) of patients, the most common of which were increased lipase (asymptomatic) (4%) and rash (3%). TRAEs led to discontinuation of treatment in four percent of study patients. The safety profile of epacadostat plus KEYTRUDA (pembrolizumab) was generally consistent with previously reported ECHO-202 Phase 1 data and with the safety profile of KEYTRUDA monotherapy.
"The combination of KEYTRUDA and epacadostat as a treatment for multiple advanced solid tumors has shown promise in our preliminary Phase 1/2 clinical trials," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "We welcome the opportunity to collaborate with Incyte and we look forward to progressing this combination in pivotal trials."
About ECHO-202 (KEYNOTE-037)
The ECHO-202 study (NCT02178722) is evaluating the safety and efficacy of epacadostat, Incyte’s selective IDO1 inhibitor, in combination with Merck’s KEYTRUDA. Patients previously treated with anti-PD-1 or anti-CTLA-4 therapies were excluded from this trial. Enrollment is complete for the Phase 1 dose escalation (epacadostat 25, 50, 100 mg BID + KEYTRUDA 2 mg/kg IV Q3W and epacadostat 300 mg BID + KEYTRUDA 200 mg IV Q3W) and Phase 1 dose expansion (epacadostat 50, 100, and 300 mg BID + KEYTRUDA [pembrolizumab] 200 mg IV Q3W) portions of the trial. For more information about ECHO-202, visit View Source
About ECHO
The ECHO clinical trial program was established to investigate the efficacy and safety of epacadostat as a core component of combination therapy in oncology. Ongoing Phase 1 and Phase 2 studies evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors collectively plan to enroll over 900 patients in a broad range of solid tumor types as well as hematological malignancies. ECHO-301 (NCT02752074), a Phase 3 randomized, double-blind, placebo-controlled study investigating KEYTRUDA in combination with epacadostat or placebo for the treatment of patients with unresectable or metastatic melanoma, is also underway. For more information about the ECHO clinical trial program, visit www.ECHOClinicalTrials.com.
About Epacadostat (INCB024360)
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key immunosuppressive enzyme that modulates the anti-tumor immune response by promoting regulatory T cell generation and blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to avoid immune surveillance. Epacadostat is an investigational, highly potent and selective oral inhibitor of the IDO1 enzyme that regulates the tumor immune microenvironment, thereby restoring effective anti-tumor immune responses. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma. In these studies, epacadostat combined with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitor KEYTRUDA improved response rates compared with studies of the immune checkpoint inhibitors alone.
About KEYTRUDA (pembrolizumab) Injection
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 500 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.
KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single-dose vial.
KEYTRUDA (pembrolizumab) Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.
Head and Neck Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA (pembrolizumab) is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Microsatellite Instability-High (MSI-H) Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.
In adult patients with MSI-H cancer, KEYTRUDA (pembrolizumab) is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Selected Important Safety Information for KEYTRUDA (pembrolizumab)
KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.
KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.
KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA (pembrolizumab) for Grade 3 or 4 hyperthyroidism.
KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.
KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.
Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.
KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA (pembrolizumab).
Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.
KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reactions (in ≥20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and 3 patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients, the most frequent (≥2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.
In KEYNOTE-045, KEYTRUDA (pembrolizumab) was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (≥20%) in patients who received KEYTRUDA vs those who received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients, the most frequent (≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.
It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

On June 5, 2017 Heat Biologics, Inc. ("Heat") (Nasdaq: HTBX), a leader in the development of novel therapies designed to activate a patient’s immune system against cancer, reported that it presented a poster from the Phase 2 trial evaluating HS-410 (vesigenurtacel-L) in combination with standard of care, Bacillus Calmette-Guérin (BCG), in the treatment of non-muscle invasive bladder cancer at the 2017 ASCO (Free ASCO Whitepaper) (American Association of Clinical Oncologists) Annual Meeting in Chicago yesterday (Press release, Heat Biologics, JUN 5, 2017, View Source [SID1234519384]).

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Study findings suggest that immune response activity, as measured by ELISPOT analysis on peripheral blood lymphocytes drawn from low-dose HS-410 patients over the course of their treatment, demonstrates a substantially better recurrence free survival outcome than BCG alone. In the trial, 100% of the patients who showed a positive ELISPOT immune response to the low-dose therapy remained disease-free after 18 months. This data compares favorably to the 80% disease-free rate in the placebo arm and is consistent with data reported in March for our lung cancer trial where 100% of the patients with positive clinical positive clinical benefit and tumor reduction also showed positive ELISPOT immune response to HS-110.

Jeff Hutchins, Ph.D., Heat’s Chief Scientific Officer and Senior Vice President of Preclinical Development, commented, "We are encouraged by the findings of this study as the data continues to mature, which gives us further confidence in the ability of our approach to mount an immune response and protect patients as part of a combination approach in immunotherapy. We look forward to continuing to progress our HS-110 in combination with Bristol-Myers Squibb’s checkpoint inhibitor nivolumab in lung cancer."

As previously announced, the Company discontinued its HS-410 program in order to focus on current and future checkpoint and T cell co-stimulator combination programs, including its HS-110 Phase 2 lung cancer program in combination with Bristol-Myers Squibb’s checkpoint inhibitor nivolumab in lung cancer.